CN102036946A - Co-crystals of duloxetine and Cox-inhibitors for the treatment of pain - Google Patents
Co-crystals of duloxetine and Cox-inhibitors for the treatment of pain Download PDFInfo
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- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
- C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
Abstract
The present invention relates to co-crystals of duloxetine and co-crystal formers selected from COX-INHIBITORs, processes for preparation of the same and their uses as medicaments or in pharmaceutical formulations, more particularly for the treatment of pain. Specific COX-INHIBITORS are naproxen and tolmetin.
Description
The present invention relates to duloxetine and be selected from the eutectic of the eutectic precursor of COX-inhibitor class, its preparation method with and as medicine or the application in pharmaceutical preparation, relate more particularly to its application in treatment pain.
Pain is a kind of complex reaction, and it is divided into sensibility pain, spontaneous pain, motion pain and emotion composition pain on function.The sensation aspect includes closes the information that stimulates position and intensity, and the adaptability composition can be considered to activate inherent regulating pain and behavior plan is used for fugue reaction (escaping reaction).As if the emotion composition comprises pain sense of discomfort and the evaluation that stimulate to threaten, and the negative feeling that is caused by the memory and the content of pain stimulation.
In general, pain condition can be divided into chronic and acute pain.Chronic pain comprises neuropathic pain and chronic inflammatory diseases pain, and the pain of for example sacroiliitis, or unknown sources is as fibromyalgia.Acute pain usually occur in non-nervous tissue injured after, for example because the tissue injury due to surgical operation or the inflammation, or migraine.
(+)-(S)-N-methyl-N-[3-(naphthalene-1-base oxygen base)-3-(2-thienyl)-propyl group] amine, its INN name is called duloxetine, be also referred to as (+)-(S)-duloxetine or (S)-duloxetine, known its is effective serotonin and noradrenaline reuptake inhibitor (SNRI).Duloxetine on the market is used for the treatment of various diseases, as anxiety and depression, also comprises pain, especially diabetic peripheral neuropathy.
Duloxetine/(S)-duloxetine
Duloxetine is a kind of medicine commonly used.Conventional route of administration is the oral capsule that contains enteric coating coatedparticles form duloxetine hydrochloride, and wherein the application dosage of active duloxetine is 20,30 and 60mg.It is necessary that enteric coating coats, because duloxetine has acid labile, therefore has rotten danger under the stomach sour environment.The major side effects that in 10% to 20% patient, takes place be feel sick, drowsiness, insomnia and dizzy.As mentioned above, as widely used medicine, thereby have the continuous needs that its performance realizes multiple effect that improve, these effects are for example for prescription improvement, effectiveness improve, side effect reduces (for example by reducing necessary dosage etc.).
Therefore, the purpose of this invention is to provide the novel method of improving the duloxetine performance, especially about the performance of treatment pain aspect, it is realized by the novel patent medicine form (drugable forms) that duloxetine is provided.
Improvements/the advantage of the special expectation of this novel patent medicine form should comprise:
The improvement of physicochemical property, thus help preparation, manufacturing, or promote to absorb and/or bioavailability (bioavailability):
Therefore
Specific activity is higher mutually with duloxetine base or hydrochloride; Or
Provide duloxetine and its itself to have the form of the promoting agent of useful pharmacological effect, thereby make final activeconstituents have dosage/weight ratio (relation relation) efficiently, or even
Make the duloxetine to use lower therapeutic dose and other promoting agent or these two;
By being made up, duloxetine and other promoting agent in same novel patent medicine form, have synergistic effect (synergistic effect, synergy); Or
Further
Can easily obtain, be easy to make, or
Make preparation have more handiness, or help its preparation,
Highly solvable, thus make dissolution rate higher, if especially be dissolved in the water-based physiological environment, or
Reduce water absorbability (hygroscipicity);
Improve stability;
Allow the new approach that gives;
And
Duloxetine and chemically common inconsistent promoting agent are made up in same preparation, even closely contact, and needn't isolate duloxetine; Embodiment will comprise acidic active agent and acid labile duloxetine;
Or it is final
Side effect, especially severe side effect due to the duloxetine are minimized/reduce.
It would be desirable, this novel patent medicine form should merge in these advantages more than a kind of, or or even most of advantage.
Realized above-mentioned purpose by the novel eutectic that duloxetine is provided.Found that duloxetine can form eutectic with COX-inhibitor class.If compare with independent duloxetine, these eutectics demonstrate improved performance, and good analgesic activities.Thus obtained eutectic has specific stoichiometric relation, and it depends on the structure of every kind of eutectic precursor.In appropriate circumstances, another advantage of these novel solid patent medicine forms is possible realize certain adjusting of pharmacological effect.Can form polymorphic form (crystallinepolymorphs), solvate, hydrate and amorphous form although it has been generally acknowledged that API (active pharmaceutical composition) for many years, know little about it yet which API can form eutectic about such as duloxetine.Eutectic is the crystalline form of specific type, thereby it provides the new way that is used to regulate the API form and regulates the API performance.Eutectic contains API and at least a other composition cocrystallization.Can the selection of described other compositions be helped to determine to form eutectic and what kind of performance eutectic will have.Polymorphic form (polymorph), solvate, hydrate or amorphous form as API can be regulated stability, solvability and water absorbability, and eutectic can be regulated these performances equally.
Therefore, main purpose of the present invention is the eutectic that comprises the eutectic precursor of duloxetine and at least a COX-of being selected from inhibitor class.The group of COX-inhibitor class comprises NSAID (NSAID (non-steroidal anti-inflammatory drug)).
" COX-inhibitor " suppresses the activity of cyclo-oxygenase (COX) based on it and defines, and this activity is one of two kinds of activity of prostaglandin endoperoxides synthetic enzyme (PGHS).PGHS is the key enzyme of prostaglandin(PG) approach.On this significance of application, some preferred eutectic precursors are those COX-inhibitor class/NSAID with carboxylic acid functional, the example comprise salicylate, aminobenzoate, Arylacetic acids/aryl alkanoic acid and arylpropionic acid, also comprise former times dry goods (Coxib).
" (duloxetine) patent medicine form " used herein is defined as the arbitrary form (salt, metamict crystals, solution, dispersion, mixture etc.) that duloxetine can be taked, but it still can be formulated into pharmaceutical preparation, this pharmaceutical preparation can be used as the medicament (medicament) of treatment disease or symptom, especially pain.
" eutectic " used herein is defined as comprising the crystalline material of two or more compounds, and wherein at least two kinds keep together by weak interaction, and wherein at least a compound is the eutectic precursor.Weak interaction is defined as neither ionic interaction neither covalent interaction, for example comprises: hydrogen bond, Van der Waals force and π-π interacts.The solvate that does not further comprise the duloxetine of eutectic precursor is not according to eutectic of the present invention.Yet eutectic can comprise one or more solvate molecules in lattice.For the sake of clarity, must emphasize difference between crystalline salt and the eutectic here.The API that is incorporated into another compound formation salt by ionic interaction can think according to a kind of " compound " of the present invention, but itself can not think two kinds of compounds.
In scientific literature, some are arranged at present about the eutectiferous discussion of correct use term (for example, referring to Desiraju, CrystEngComm, 2003,5 (82), 466-467 and Dunitz, CrystEngComm, 2003,5 (91), 506).Nearest one piece of article (Zwarotko, the Crystal Growth﹠amp of Zawarotko; Design, Vol.7, No.1,2007,4-9) provided eutectiferous definition, it is consistent with the definition that above provides, so it also is the definition according to " eutectic " of the present invention.According to this piece article, " eutectic is the polycomponent crystal, and wherein all components is a solid with its respective pure form at ambient temperature.These components constitute target molecule or ion and molecule eutectic precursor; When in eutectic, they coexist on molecular level in single crystal ".
IASP (IASP) is defined as " pain " " unhappiness sensation or the emotional experience relevant with reality or potential tissue injury ", or be described (IASP about this damage, Classification of chronic pain, second edition, IASP Press (2002), 210).Although pain is subjectivity always, its cause or syndromes can classify.
According to IASP, " allodynia " is defined as " owing to not causing the pain that the stimulation of pain causes usually " (IASP, Classification of chronic pain, second edition, IASP Press (2002), 210).Although the symptom most probable of allodynia is got in touch the symptom for neuropathic pain, but situation might not be like this, therefore the symptom that allodynia exists and neuropathic pain is irrelevant, however this can cause allodynia than neuropathic pain in some region generating widely.
IASP has further described the following difference (IASP between " allodynia ", " hyperpathia (hyperalgesia) " and " hyperpathia (hyperpathia) ", Classification of chronic pain, second edition, IASP Press (2002), 212):
| Allodynia | Threshold value reduces | Stimulate different with reactive mode |
| Hyperpathia | Increased response | Stimulate identical with speed of reaction |
| Hyperpathia | Threshold value raises; Increased response | Stimulation and speed of reaction can be identical or different |
According to IASP, " neuropathy " is defined as " neural primary lesion or dysfunction " (IAS P, Classification of chronic pain, second edition, IASP Press (2002), 211).Neuropathic pain may have maincenter or outer perigene.
In an eutectiferous embodiment of the present invention, one of eutectic precursor or eutectic precursor have at least one and come free ether, thioether, alcohol, sulfydryl, aldehyde, ketone, thioketones, nitric ether, phosphoric acid ester, thiophosphatephosphorothioate, ester, thioesters, sulfuric ester, carboxylic acid, phosphonic acids, phospho acid, sulfonic acid, acid amides, primary amine, secondary amine, ammonia, tertiary amine, thiocyanate-, cyanamide, oxime, nitrile, diazo, Organohalogen compounds (organohalide), nitro, the s-heterocycle, thiophene, the n-heterocycle, the pyrroles, the o-heterocycle, furans, epoxide, superoxide, hydroxamic acid, functional group in the group that imidazoles and pyridine constitute;
Preferred wherein eutectic precursor has the functional group at least one group of coming free alcohol, sulfydryl, ester, carboxylic acid, primary amine, secondary amine, tertiary amine formation.
In an eutectiferous embodiment of the present invention, one of eutectic precursor or eutectic precursor have at least one and come free ether, thioether, alcohol, sulfydryl, aldehyde, ketone, thioketones, nitric ether, phosphoric acid ester, thiophosphatephosphorothioate, ester, thioesters, sulfuric ester, carboxylic acid, phosphonic acids, phospho acid, sulfonic acid, acid amides, primary amine, secondary amine, ammonia, tertiary amine, thiocyanate-(ester), cyanamide, oxime, nitrile, diazo, Organohalogen compounds, nitro, the s-heterocycle, thiophene, the n-heterocycle, the pyrroles, the o-heterocycle, furans, epoxide, hydrogen peroxide, hydroxamic acid, functional group in the group that imidazoles and pyridine constitute;
One of preferred wherein eutectic precursor or eutectic precursor have the functional group at least one group of coming free alcohol, sulfydryl, ester, carboxylic acid, primary amine, secondary amine, tertiary amine formation.
Most preferably wherein one of eutectic precursor or eutectic precursor have at least one and are the functional group of carboxylic acid.
In another embodiment, one of eutectic precursor or eutectic precursor have at least one and are selected from functional group in the group that is made of alcohol, ester or carboxylic acid.In another embodiment, one of eutectic precursor or eutectic precursor have at least one and are the functional group of carboxylic acid.
In another embodiment of eutectic precursor of the present invention, select (one or more) eutectic precursor by this way, that is, if make and to compare with the mixture of corresponding promoting agent with independent duloxetine or duloxetine,
Eutectiferous solvability improves; And/or
Eutectiferous dose response improves; And/or
Eutectiferous usefulness improves; And/or
Eutectiferous dissolution rate (dissolution) improves; And/or
Eutectiferous bioavailability improves; And/or
Eutectiferous stability improves; And/or
Eutectiferous water absorbability reduces; And/or
The reduction of eutectiferous various informative property; And/or
Eutectiferous form is adjusted.
The mixture of " duloxetine and (one or more) corresponding promoting agent " is defined as the mixture of (one or more) promoting agent ((one or more) eutectic precursor) and duloxetine among the discussion, it only is a physical mixture, interact without any coupling (coupling) between each component, therefore comprise that neither salt does not comprise another kind of eutectic yet.
Term " salt " is interpreted as representing the duloxetine or the eutectic precursor of arbitrary form of the present invention, wherein is assumed to ionic species or has electric charge and coupling has gegenion (positively charged ion or negatively charged ion) or in solution.Also can be regarded as duloxetine or eutectic precursor and other molecule and ionic mixture thus, especially by ionic interaction compound mixture.This also comprises physiologically acceptable salt.
Term of the present invention " solvate " is interpreted as representing the duloxetine or the eutectic precursor of arbitrary form, wherein compound is connected in it by non-covalent in conjunction with another molecule (most likely polar solvent), it especially comprises hydrate and alcoholic solvent thing, for example methanol solvate thing.
In eutectiferous another embodiment of the present invention, the mol ratio between at least a in duloxetine and eutectic precursor or the eutectic precursor is not 1.This advantage that may have is: can be in having the fixed dosage that eutectic has superiority mol ratio such as non-between development duloxetine and (one or more) promoting agent.
The eutectic precursor is selected from COX-inhibitor class (it comprises NSAID), and preferably those have the COX-inhibitor of carboxylic acid functional.Preferred embodiment comprise salicylate, anthranilate, Arylacetic acids/aryl alkanoic acid and arylpropionic acid.Therefore, a preferred embodiment of the present invention is the eutectic that comprises the eutectic precursor of duloxetine and at least a NSAID of being selected from (NSAID that preferably has carboxylic acid functional).Another preferred implementation of the present invention is to comprise duloxetine and at least a NSAID of being selected from, be selected from salicylate, the eutectic of eutectic precursor of anthranilate, Arylacetic acids/aryl alkanoic acid or arylpropionic acid.Other preferred implementation of the present invention be a) comprise duloxetine and at least a be selected from into salicylate the eutectic of eutectic precursor of NSAID; B) comprise duloxetine and at least a eutectic that is selected to the eutectic precursor of the NSAID of anthranilate; C) comprise duloxetine and at least a eutectic that is selected to the eutectic precursor of the NSAID of Arylacetic acids/aryl alkanoic acid; Or d) comprises duloxetine and at least a eutectic that is selected to the eutectic precursor of the NSAID of arylpropionic acid.
Salicylate example have: acetylsalicylic acid, diflunisal, ethenzamide, salicylic amide, Triflusal, Fosfosal and Win-11450.The example of anthranilate has: etofenamate, Flufenamic Acid, meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid.The example of Arylacetic acids/aryl alkanoic acid has: acemetacin, oxametacin, indomethacin glucosamide, proglumetacin, bufexamac, diclofenac, W-7320 (Alcofenac), Aceclofenac, indomethacin, lonazolac, sulindac, Tolmetin, Amtolmetin Guacil, N-22, Bromfenac, nabumetone, fentiazac and felbinac.The example of arylpropionic acid has: flurbiprofen, flurbiprofen axetil, Ibuprofen BP/EP, Ketoprofen, Naproxen Base, tiaprofenic acid, zaltoprofen, pirprofen, fenoprofen, Vedaprofen, nepafenac (Nepafenac), amfenac and clidanac.
In eutectiferous another embodiment of the present invention, one of eutectic precursor or eutectic precursor are selected from:
Acetylsalicylic acid, diflunisal, ethenzamide, salicylic amide, Triflusal, Fosfosal, Win-11450, etofenamate, Flufenamic Acid, meclofenamic acid, mefenamic acid, niflumic acid, tolfenamic acid, acemetacin, oxametacin, indomethacin glucosamide, proglumetacin; bufexamac; diclofenac; W-7320; Aceclofenac; indomethacin; lonazolac; sulindac; Tolmetin; Amtolmetin Guacil; N-22; Bromfenac; nabumetone; fentiazac; felbinac; flurbiprofen; flurbiprofen axetil; Ibuprofen BP/EP; Ketoprofen; Naproxen Base; tiaprofenic acid; zaltoprofen; pirprofen; fenoprofen; Vedaprofen; nepafenac; amfenac and clidanac; Or its steric isomer, salt or metabolite.
Other example of NSAID is a former times dry goods (Coxib), selective COX-2-2 inhibitor.Therefore, another preferred implementation of the present invention is to comprise duloxetine and at least a eutectic of eutectic precursor of NSAID that is selected to the former times dry goods.Former times, the example of dry goods had: celecoxib, rely on former times cloth (support is examined former times), Luo Mei former times cloth (Lu Mikao former times), Parecoxib (parecoxib), rofecoxib, cut down ground former times cloth (valdecoxib) and western miaow former times cloth (cimicoxib).
Other example of eutectic precursor is the p-aminophenyl amphyl.Therefore, another preferred implementation of the present invention be comprise duloxetine and at least a be selected from the p-aminophenyl amphyl the eutectic of eutectic precursor.The p-aminophenyl amphyl example have: paracetamol, propacetamol and phenidine (Phenidine).
In eutectiferous another embodiment of the present invention, one of eutectic precursor or eutectic precursor are selected from:
Acetylsalicylic acid, diflunisal, ethenzamide, salicylic amide, Triflusal, Fosfosal, Win-11450, paracetamol, propacetamol, phenidine, etofenamate, Flufenamic Acid, meclofenamic acid, mefenamic acid, niflumic acid, tolfenamic acid, acemetacin, oxametacin, indomethacin glucosamide, proglumetacin; bufexamac; diclofenac; W-7320; Aceclofenac; indomethacin; lonazolac; sulindac; Tolmetin; Amtolmetin Guacil; N-22; Bromfenac; nabumetone; fentiazac; felbinac; flurbiprofen; flurbiprofen axetil; Ibuprofen BP/EP; Ketoprofen; Naproxen Base; tiaprofenic acid; zaltoprofen; pirprofen; fenoprofen; Vedaprofen; nepafenac; amfenac; clidanac; Sulpyrine; propyl group quinizine; recheton; mofebutazone; crovaril; Phenylbutazone; Azapropazone; isoxicam; lornoxicam; piroxicam; tenoxicam; ketorolac; Soz 43-715; Evil promazine; ditazole; R-ETODOLAC; meloxicam; nimesulide; celecoxib; rely on former times cloth; Luo Mei former times cloth; Parecoxib; rofecoxib; cut down ground former times cloth; western miaow former times cloth; Or its steric isomer, salt or metabolite;
Or
Acetylsalicylic acid, diflunisal, ethenzamide, salicylic amide, Triflusal, Fosfosal, Win-11450, paracetamol, propacetamol, phenidine, etofenamate, Flufenamic Acid, meclofenamic acid, mefenamic acid, niflumic acid, tolfenamic acid, acemetacin, oxametacin, indomethacin glucosamide, proglumetacin; bufexamac; diclofenac; W-7320; Aceclofenac; indomethacin; lonazolac; sulindac; Tolmetin; Amtolmetin Guacil; N-22; Bromfenac; nabumetone; fentiazac; felbinac; flurbiprofen; flurbiprofen axetil; Ibuprofen BP/EP; Ketoprofen; Naproxen Base; tiaprofenic acid; zaltoprofen; pirprofen; fenoprofen; Vedaprofen; nepafenac; amfenac; clidanac; Sulpyrine; propyl group quinizine; recheton; mofebutazone; crovaril; Phenylbutazone; Azapropazone; isoxicam; lornoxicam; piroxicam; tenoxicam; ketorolac; Soz 43-715; Evil promazine; ditazole; R-ETODOLAC; meloxicam; nimesulide; celecoxib; rely on former times cloth; Luo Mei former times cloth; Parecoxib; rofecoxib; cut down ground former times cloth; western miaow former times cloth; Bermoprofen; Pelubiprofen; Tenosal; Aceneuramic acid; Pirazolac; Xi Nuoluofen (Xinoprofen); Fluorine is spreaded out sweet smell; Anirolac; Zoliprofen; Bromfenac; Pemedolac; Dexpemsdolac; Bindarit; Romazarit; (S)-Naproxen Base; Tiaprofenic acid; Fenbufen; Fenoprofen; Fluorine is spreaded out sweet smell; Taisho); Or its steric isomer, salt or metabolite;
Preferentially be selected from:
Acetylsalicylic acid; Triflusal; HTB (2-hydroxyl-4-trifluoromethylbenzoic acid); Diflunisal; Meclofenamic acid; Mefenamic acid; Niflumic acid; Flufenamic Acid; Diclofenac; Lonazolac; Acemetacin; Indomethacin; Tolmetin; Sulindac; R-ETODOLAC; Ketorolac; Flurbiprofen; (RS)-flurbiprofen; Esflurbiprofen; Ibuprofen BP/EP; (RS)-Ibuprofen BP/EP; S-(+)-Ibuprofen BP/EP; Ketoprofen; (rac)-Ketoprofen (racemize-Ketoprofen); R-(-)-Ketoprofen; Bermoprofen; Pelubiprofen; Tenosal; Aceneuramic acid; Pirazolac; Xi Nuoluofen; Fluorine is spreaded out sweet smell; Anirolac; Zoliprofen; Bromfenac; Pemedolac; Dexpemsdolac; Bindarit; Romazarit; Naproxen Base; (S)-Naproxen Base; Tiaprofenic acid; Fenbufen; Fenoprofen; Fluorine is spreaded out sweet smell; Taisho); Or its steric isomer, salt or metabolite;
More preferably acetylsalicylic acid, paracetamol; Naproxen Base, (S)-Naproxen Base; Ibuprofen BP/EP, (RS)-Ibuprofen BP/EP, S-(+)-Ibuprofen BP/EP; One of or its salt.
In general, all these eutectic precursors with at least one stereogenic centres are understood to include its racemic form or in this article as diastereomer or enantiomer or its mixture.
As the COX-inhibitor of being paid close attention to a kind of height of the eutectic precursor of duloxetine is the streat drug Naproxen Base, its chemistry (S)-(6-methoxyl group-2-naphthyl) propionic acid by name, and it also is described to physiologically acceptable salt.Its empirical formula is C
14H
14O
3, Mp is 153 ℃, pKa is 4.2.
Naproxen Base
Therefore, another aspect very preferably of the present invention relates to eutectic of the present invention, and wherein the eutectic precursor is Naproxen Base, its enantiomer or its salt.Refer in particular to eutectic of the present invention, wherein the eutectic precursor is (S)-Naproxen Base.
Hereinafter illustrate in greater detail duloxetine with (S)-Naproxen Base forms eutectic.Usually the eutectic that obtains has specific stoichiometric relation, and it depends on whenever-structure of eutectic precursor.Forming under eutectiferous particular case with (S)-Naproxen Base as the eutectic precursor, the molecular ratio between duloxetine and (S)-Naproxen Base is 2 to 3.
In this specific eutectic of duloxetine of the present invention and (S)-Naproxen Base, start from 124 ℃ corresponding to the heat absorption spike (endothermic sharp peak) of fusing point.
This specific eutectic at duloxetine of the present invention and (S)-Naproxen Base demonstrates in the X-ray powder diffraction collection of illustrative plates, 12.889,10.733,10.527,9.194,8.541,7.594,7.430,6.656,6.444,6.082,5.975,5.754,5.436,5.346,5.259,5.182,5.131,4.953,4.930,4.817,4.766,4.739,4.690,4.654,4.638,4.597,4.434,4.293,4.266,4.174,4.068,4.005,3.984,3.940,3.886,3.795,3.769,3.735,3.715,3.641,3.577, with 3.533 places have the d of being expressed as value (with
Meter) peak:
This specific eutectic according to duloxetine of the present invention and (S)-Naproxen Base also has the triclinic(crystalline)system structure cell, and it has following size:
α＝107.477(3)°
β＝99.792(3)°
γ＝95.382(2)°
As the COX-inhibitor of highly being paid close attention to the another kind of the eutectic precursor of duloxetine is the streat drug Tolmetin; its chemical name is [1-methyl-5-(4-methyl benzoyl)-1H-pyrroles-2-yl] acetate], it also is described to physiologically acceptable salt.
Tolmetin
Therefore, another aspect very preferably of the present invention relates to eutectic of the present invention, and wherein the eutectic precursor is Tolmetin or its salt.
Hereinafter illustrate in greater detail duloxetine and Tolmetin and form eutectic.Usually the eutectic that obtains has specific stoichiometric relation, and it depends on the structure of each eutectic precursor.Forming under eutectiferous particular case with Tolmetin as the eutectic precursor, the molecular ratio between duloxetine and the Tolmetin is 1 to 2.
In this specific eutectic of duloxetine of the present invention and Tolmetin, start from 111 ℃ corresponding to the heat absorption spike of fusing point.
This specific eutectic in duloxetine of the present invention and Tolmetin demonstrates in the X-ray powder diffraction collection of illustrative plates, have at 13.774,12.845,11.510,9.146,8.909,8.462,7.662,6.856,6.435,6.329,6.019,5.881,5.715,5.571,5.259,5.010,4.928,4.888,4.569,4.443,4.274,4.216,4.136,4.032,3.951,3.896,3.830 and 3.757 places the d of being expressed as value (with
Meter) peak.
Of the present invention eutectiferous another preferred embodiment in, the eutectic precursor is Ibuprofen BP/EP, its enantiomer or its salt.
In eutectiferous another preferred implementation of the present invention, the eutectic precursor is (S)-Ibuprofen BP/EP.
Another embodiment of the invention relates to and is used for producing eutectiferous method of the present invention as mentioned above, and it may further comprise the steps:
(a) the eutectic precursor is dissolved or suspended in the solvent; With
(b) this solution or dispersion are heated to above envrionment temperature and are lower than the temperature of the boiling point of this solution or dispersion;
(c) in step (a), will be dissolved in the solvent together as the duloxetine of free alkali or salt afterwards or before;
(d) solution of (c) is joined in the solvent of (b) of heating and and mix it;
(e) mixing solutions/dispersion with step (d) is cooled to envrionment temperature;
(f) leach the eutectic that obtains.
Another embodiment of the invention relates to and is used for producing eutectiferous method of the present invention as mentioned above, and it may further comprise the steps:
(possibility I):
(a) the eutectic precursor is dissolved or suspended in the solvent; With
(b) this solution or dispersion are heated to above envrionment temperature and are lower than the temperature of the boiling point of this solution or dispersion;
(c) in step (a), will be dissolved in the solvent together as the duloxetine of free alkali or salt afterwards or before;
(d) solution of (c) is joined in the solvent of (b) of heating and and mix it;
Or (possibility II):
(a) eutectic precursor and duloxetine are dissolved or suspended in the solvent; With
(b) this solution or dispersion are heated to above envrionment temperature and are lower than the temperature of the boiling point of this solution or dispersion;
(d) solvent is joined in the solvent of (b) of heating and and mix it;
(for possibility I and II) then
(e) mixing solutions/dispersion with step (d) is cooled to envrionment temperature;
(f) leach the eutectic that obtains.
" envrionment temperature " is defined as 20 ℃ to 25 ℃ temperature in this article, is preferably 20 ℃.
The solvent that can be used for present method comprises water or organic solvent, preferentially be selected from acetone, isobutyl acetate, acetonitrile, ethyl acetate, 2-butanols, methylcarbonate, chlorobenzene, butyl ether, Di Iso Propyl Ether, dimethyl formamide, ethanol, water, hexane, Virahol, methyl ethyl ketone, methyl alcohol, methyl tertiary butyl ether, propione, toluene and 1,1, the solvent of 1-trichloroethane, most preferably comprise alcohol, as ethanol.Preferred but nonessential is that the solvent of step among the possibility I (a) and (c) is identical.
Molecular ratio between duloxetine and the eutectic precursor between 10: 1 to 1: 10, preferred 5: 1 to 1: 5, more preferably 3: 1 to 1: 3, most preferably 1: 1 to 1: 2.
Preferably duloxetine-the solution in (possibility I) step (c) or (possibility II) step (a) has the concentration between 3 to 0.01mM.
Eutectic of the present invention partly be have the pain relieving performance, often worldwide life-time service know medicine.Therefore, another object of the present invention is to comprise eutectiferous medicine of the present invention.
Therefore, the invention still further relates to comprise at least a eutectic of the present invention as mentioned above and optionally one or more medicines can accept vehicle medicine (medicament, medicament).
The invention still further relates to a kind of pharmaceutical composition, it is included in the eutectic of the present invention that physiology can be accepted the treatment significant quantity in the medium.Physiology can be accepted medium and be defined as and especially comprise the acceptable auxiliary substance of medicine (additives/excipients), and especially those are applicable to the auxiliary substance of solid pharmaceutical preparation, and wherein one or more can be the part of pharmaceutical preparation.
The association list of two kinds of activeconstituentss reveals several advantages in the same crystal.By being connected, they usually bring into play performance as single chemical substance (chemical entity), thereby help treatment, preparation, dosage etc.In addition, because duloxetine and eutectic precursor all are effective pain killers, these eutectics are highly suitable for treating pain, especially also can not lose any activity/weight by the gegenion of the no medical of interpolation when in the salt at no API.In addition, these two kinds of activeconstituentss (in treatment pain, also may be in various other diseases of treatment or symptom especially) in treatment complement one another.Therefore, with respect to the present technique field, eutectic of the present invention has multiple advantage really concurrently.
Another advantage be two kinds of activeconstituentss be combined into a kind of predetermined substance (kind, as if species), it allows better medicament dynamic metabolism/pharmacodynamics (PKPD), it also comprises and passes blood brain barrier better, and helps to treat pain.
Generally speaking, use in the eutectiferous embodiment of duloxetine (for example, being used for the treatment of pain etc.) at great majority, these eutectics can be formulated into pharmaceutical preparation or medicine easily.Therefore, the eutectiferous desirable advantage of duloxetine is shown as the pharmaceutical properties and the characteristic of improvement, especially when comparing with free alkali or duloxetine hydrochloride.Therefore, the eutectic desired display of duloxetine of the present invention goes out at least a, preferred multiple following characteristic:
Has very little particle size, for example from 300 μ m or lower; Or
Substantially do not take place to reunite and/or keep not reuniting substantially; Or
Water absorbability reduction or water absorbability are not strong; Or
Help to prepare controlled release or quick-release (immediate release) preparation; Or
Has high chemical stability; Or
If offer the patient, then
On blood levels, reduce between object (subject) with in the object and change; Or
Demonstrate good uptake rate (for example, blood plasma level or AUC raise); Or
Demonstrate higher maximum plasma concentration (for example, C
Max); Or
Demonstrate the time (t that reaches peak drug concentration in the blood plasma
Max) reduce; Or
Demonstrate the transformation period (t of compound
1/2) change, no matter in which kind of direction (trend all is preferred on direction) in this change.
Medicine of the present invention or pharmaceutical composition can be for being suitable for being applied to any form of people and/or animal, and preferred people comprises baby, children and adult, and it can be by standard program production well known by persons skilled in the art.Medicine of the present invention for example can give by non-enteron aisle, comprises muscle, intraperitoneal or intravenous injection, saturating mucous membrane or sublingual administration; Or oral area, comprise with tablet, ball, particle, capsule, lozenge, water or oil solution, suspension, emulsion, spraying or with the dry powder form that reconstitutes giving with liquid medium.
Typically, medicine of the present invention can comprise eutectic that one or more this paper of 1-60% by weight limit and one or more auxiliary substances (additives/excipients) of 40-99% by weight.
Composition of the present invention also can be local or be given by suppository.
Humans and animals every day dosage can according to based on its separately the factor or the other factors of kind change, as age, sex, body weight or severity extent etc.People's dosage every day is preferably in the scope of 5 to 500 milligrams of duloxetines that give in capture process once a day or repeatedly.
Another aspect of the present invention relates to the application of eutectic of the present invention as mentioned above in treatment pain, pain is preferably acute pain, chronic pain, neuropathic pain, hyperpathia, allodynia or cancer pain, comprises diabetic neuropathy or osteoarthritis or fibromyalgia.Preferably so that medicine of the present invention or pharmaceutical compositions provide this application as mentioned above.A further aspect of the invention relates to eutectic of the present invention as mentioned above and is used for the treatment of the medicine of pain or the application in the pharmaceutical composition in manufacturing, pain is acute pain, chronic pain, neuropathic pain, hyperpathia, allodynia or cancer pain preferably, comprises diabetic neuropathy or osteoarthritis or fibromyalgia.
Another object of the present invention is a kind of method for the treatment of pain, preferred acute pain, chronic pain, neuropathic pain, hyperpathia, allodynia or cancer pain, comprise diabetic neuropathy or osteoarthritis or fibromyalgia, this method is by (or as described below aspect preferred in) as mentioned above eutectic of the present invention of q.s is provided to its patient of needs.Preferably provide eutectic of the present invention, for example with medicine of the present invention or pharmaceutical compositions as mentioned above with form suitable on the physiology.
By the present invention being described hereinafter by drawings and Examples.These explanations only are in order to give an example, and are not to limit the present invention.
Brief description of drawings
Fig. 1:
(the S)-duloxetine that analyze to obtain by SCXRD-(S)-the eutectiferous structure of Naproxen Base (2: 3).For the sake of clarity, omitted hydrogen atom (except being connected in heteroatomic hydrogen atom).
Fig. 1 has shown the structure that (the S)-duloxetine by (the S)-Naproxen Base of 3 molecules and 2 molecules forms.
Utilize the Cai Si stereoscopic microscope of polarisation to select to measure crystal by use, this crystal prepares under the inert conditions of the PFPE protection oil that immersion is used for operating.Use is equipped with APPEX 24K CCD area detector, has Mo
K αRadiating FR591 rotating anode, carry out crystalline structure as the Bruker-Nonius diffractometer of the Montel mirror of monochromator and Kryoflex cryogenic unit (T=100K) and determine.Radiation scope (Fullsphere) data gathering ω and phi scanning fully.Service routine: data gathering Apex2 is (Bruker-Nonius 2004), data reduction Saint+6.22 version (Bruker-Nonius 2001) and absorption correction SADABS V.2.10 (2003) V.1.0-22.Use 6.10 editions (Sheldrick, brother's Dettingen university (Germany), 2000) middle direct methods of implementing of SHELXTL to obtain crystallographic structural analysis, and use the XP program to carry out visual.It is follow-up by differential Fourier synthesis location and join in the atom tabulation to lose atom.Service routine SHELXTL 6.10 editions (Sheldrick, brother's Dettingen university (Germany), 2000) uses the F of all measured intensity
0 2Least-squares refinement.The non-hydrogen atom that refine is all comprises the anisotropy displacement parameter.
Fig. 2:
(S)-duloxetine-(S)-the eutectiferous x-ray diffractogram of powder spectrum of Naproxen Base (2: 3).
The sample of the about 20mg of preparation in the standard test specimen frame that uses two poly-acetic ester thin slices.Use penetrates geometric Cu
K α-radiation obtains powder diffraction spectrum in D8 Advance Series 2 θ/θ powdery diffractometry system.This system disposition has
Single photon counting PSD, germanium monochromator, 90 autochanger sample table, fixedly divergent slit and radial halfpace (radial soller).Service routine: data gathering DIFFRAC+XRD Commander V.2.4.1 with Assessment of EVA V.12.0.
Fig. 3:
(S)-duloxetine-(S)-Naproxen Base (2: 3) is eutectiferous
1H-NMR.
Fig. 3 illustrates the eutectiferous of (S)-duloxetine of being shown as 2: 3 ratios and (S)-Naproxen Base
1H-NMR analyzes.
Proton nuclear magnetic resonance analysis is recorded as in the deuterate methyl alcohol (MeOH-d4) in the Bruker Avance 400 Ultrashield NMR spectrometers that are equipped with z-gradient 5mm BBO (broadband observation) probe.The sample dissolution of 2-10mg is obtained wave spectrum in the deuterate solvent of 0.6mL.
Fig. 4:
(S)-duloxetine-(S)-the eutectiferous FT-IR spectrum of Naproxen Base (2: 3).
Fig. 4 has shown the eutectiferous infrared spectra of acquisition.
Use is equipped with the anti-ATR of MKII Golden Gate list system, writes down the FTIR spectrum as the mid-infrared light source of excitaton source and the Bruker Tensor 27 of DTGS detector.With 4cm
-1Resolving power in 32 line sweeps, obtain spectrum.
Fig. 5:
(S)-duloxetine-(S)-the eutectiferous dsc analysis of Naproxen Base (2: 3).
Fig. 5 has shown the heat analysis that has 124 ℃ of fusing points on the DSC.
In Mettler Toledo DSC822e, write down dsc analysis.To 40 μ L aluminium crucibles with little port lid, (50mL/min) is heated to 300 ℃ with 10 ℃/min from 30 ℃ under nitrogen with the samples weighing of 1-2mg.
Fig. 6:
(S)-duloxetine-(S)-the eutectiferous TG analysis of Naproxen Base (2: 3)
Fig. 6 has shown in the thermogravimetric analysis that is lower than imponderability loss under the decomposition temperature.
In Mettler Toledo SDTA851e, write down thermogravimetric analysis.To 40 μ L aluminium crucibles with little port lid, (80mL/min) is heated to 500 ℃ with 10 ℃/min from 30 ℃ under nitrogen with the samples weighing of 3-4mg.
Fig. 7:
Embodiment 1d) stability study of (S)-duloxetine HCl of Miao Shuing.
Fig. 7 has shown that (S)-duloxetine hydrochloride of obtaining is at the time of origin (dotted line) and the HPLC color atlas of (solid line) after 5 days.
Fig. 8:
Embodiment 1d) (the S)-duloxetine of Miao Shuing-(S)-eutectiferous stability study of Naproxen Base (2: 3).
Fig. 8 has shown that (S)-duloxetine of obtaining-(S)-Naproxen Base (2: 3) eutectic is at the time of origin (dotted line) and the HPLC color atlas of (solid line) after 5 days.
Fig. 9:
(S)-the eutectiferous dsc analysis of duloxetine-Tolmetin (1: 2).
Fig. 9 has shown the heat analysis that has 111 ℃ of fusing points on the DSC.
In Mettler Toledo DSC822e, write down dsc analysis.To 40 μ L aluminium crucibles with little port lid, (50mL/min) is heated to 300 ℃ with 10 ℃/min from 30 ℃ under nitrogen with the samples weighing of 1-2mg.
(S)-the eutectiferous TG analysis of duloxetine-Tolmetin (1: 2).
Fig. 9 has shown in the thermogravimetric analysis that is lower than imponderability loss under the decomposition temperature.
In Mettler Toledo SDTA851e, write down thermogravimetric analysis.To 40 μ L aluminium crucibles with little port lid, (80mL/min) is heated to 500 ℃ with 10 ℃/min from 30 ℃ under nitrogen with the samples weighing of 3-4mg.
Figure 10:
(S)-the eutectiferous x-ray diffractogram of powder spectrum of duloxetine-Tolmetin (1: 2).
The sample of the about 20mg of preparation in the standard test specimen frame that uses two poly-acetic ester thin slices.Penetrate geometric Cu in use
K αObtain powder diffraction spectrum in-radiating D8 Advance Series 2 θ/θ powdery diffractometry system.This system disposition has
Single photon counting PSD, germanium monochromator, 90 autochanger sample table, fixedly divergent slit and radial halfpace.Service routine: data gathering DIFFRAC+XRD Commander V.2.4.1 with Assessment of EVA V.12.0.
Embodiment
Embodiment 1a: acquisition (S)-duloxetine-(S)-the eutectiferous program of Naproxen Base (2: 3)
Down (472mg, 0.4mL ethanolic soln 1.59mmol) join in the 0.8mL alcohol suspension of (S)-Naproxen Base (707mg, 3.07mmol, 1.9eq. (equivalent)) of stirring with (S)-duloxetine at 70 ℃.The solution that obtains is at room temperature left standstill, and crystallization goes out white solid.Filtering suspension liquid and the solid that obtains with washing with alcohol, in 60 ℃ of vacuum (10mm Hg) thus obtained white crystalline solid in dry 18 hours, (the S)-duloxetine of 2: 3 ratios-(S)-Naproxen Base eutectic (710mg, 69% productive rate).
Embodiment 1b: acquisition (S)-duloxetine-(S)-the eutectiferous program of Naproxen Base (2: 3)
Down (26.8g, 30mL ethanolic soln 0.09mol) join (the S)-Naproxen Base of stirring, and (31.1g, 0.135mol is in 50mL alcohol suspension 1.5eq.) with (S)-duloxetine at 70 ℃.The solution that obtains is at room temperature left standstill, and crystallization goes out white solid.Filtering suspension liquid and the solid that obtains with washing with alcohol, in 50 ℃ of vacuum (10mm Hg) thus obtained white crystalline solid in dry 7 hours, (the S)-duloxetine of 2: 3 ratios-(S)-Naproxen Base eutectic (55.6g, 96% productive rate).The eutectic that obtains among this eutectic and the embodiment 1a is identical.
Embodiment 1c:
By 1: 1 to 1: 2 duloxetine ((S)-duloxetine) and (S)-mixture of Naproxen Base begins, and obtains (S)-duloxetine-(the S)-Naproxen Base eutectic according to embodiment 1a and 1b.Except the example of embodiment 1a and 1b, determine for obtaining the most effectively solvent of eutectic thereby screened different solvents.Following solvent can produce the eutectic with duloxetine: acetone, isobutyl acetate, acetonitrile, ethyl acetate, 2-butanols, methylcarbonate, chlorobenzene, butyl ether, Di Iso Propyl Ether, ethanol, water, hexane, Virahol, methyl ethyl ketone, methyl alcohol, methyl iso-butyl ketone (MIBK), methyl tertiary butyl ether, propione, toluene, DMF, hexanaphthene and 1,1, the 1-trichloroethane.The eutectic that produces among the eutectic that forms under every kind of situation and embodiment 1a and the 1b is identical.
Eutectiferous sign:
By
1(S)-duloxetine that the detailed sign of H-NMR, FTIR, X-ray diffraction, DSC and TG obtains according to embodiment 1-(S)-Naproxen Base (2: 3) eutectic (seeing Fig. 1 to 6).
The value of specific rotation is [α]
26 D=+74.5 ° (c=1.00, MeOH)
Analyze by monocrystalline X-ray diffraction (SCXRD) and fully to have determined structure: shown among Fig. 1 by 3 molecules (S)-Naproxen Base and structure that 2 molecules (S)-duloxetine forms.For the sake of clarity, omitted hydrogen atom (except being connected in heteroatomic hydrogen atom).
Fig. 2 has shown eutectiferous powder x-ray diffraction (PXRD) collection of illustrative plates of (S)-duloxetine and (S)-Naproxen Base.Describe the peak that is expressed as the d value in the table 2 in detail.
Table 1:(S)-eutectiferous PXRD of duloxetine and (S)-Naproxen Base
Fig. 3 illustrates the eutectiferous of (S)-duloxetine of being shown as 2: 3 ratios and (S)-Naproxen Base
1H-NMR analyzes.
1H NMR (400MHz, d4-methyl alcohol) δ: 1.50 (d, J=7Hz, 9H), 2.38 (m, 2H), 2.56 (m, 2H), 2.66 (s, 6H), 3.13 (m, 2H), 3.23 (m, 2H), 3.75 (q, J=7Hz, 3H), 3.88 (s, 9H), 5.88 (dd, J=5Hz, J=8Hz, 2H), 6.92 (d, J=8Hz, 2H), 6.94 (dd, J=3Hz, J=5Hz, 2H), 7.07 (dd, J=3Hz, J=9Hz, 3H), 7.12 (d, J=3Hz, 2H), 7.16 (d, J=3Hz, 3H), 7.27 (t, J=8Hz, 2H), 7.32 (dd, J=1Hz, J=5Hz, 2H), 7.41 (d, J=8Hz, 2H), 7.44-7.51 (m, 7H), 7.67 (m, 9H), 7.79 (m, 2H), 8.28 (m, 2H).
Fig. 4 has shown eutectiferous infrared spectrogram of such acquisition.
Heat is analyzed and have been shown the fusing point (Fig. 5) that is positioned at 124 ℃ on the DSC, does not detect weight loss (Fig. 6) under the decomposition temperature being lower than in TGA.
In following table 3, provide (S)-duloxetine-(S)-eutectiferous crystal data of Naproxen Base (2: 3) and structure refinement (structure refinement) to resolve.
Table 2. (S)-duloxetine-(S)-eutectiferous crystal data of Naproxen Base (2: 3) and structure refinement parsing
Embodiment 1d: determine eutectiferous stability of the present invention:
Purpose is to measure eutectiferous stability of the present invention, and itself and a kind of duloxetine HCL stability are compared.In document (WO 2007105021), described in test and contained in the process of stability of tablet of duloxetine, in the molecular transposition process, produced degraded product.At strong inorganic acid, exist down as HCl and HBr, this process strengthens.The purpose of this research is to carry out relative stress (comparativestress) test of (S)-duloxetine-(S)-Naproxen Base (2: 3) eutectic under 60 ℃/75%RH.
Exposure condition
The 25mg sample of each product of preparation is uniformly coated on the 5cm culture dish, preserves with porose paper membrane closure, goes through 5 days in climatic chamber Heraeus HC033.
Detect degraded product by HPLC
Chromatographic condition: post: Sunfire C18,3.5 μ m, 100*4.6mm; Detect: UV 230nm; Flow velocity: 1ml/min.Moving phase: A) 63% (0.02M KH
2PO
4, pH 2.5), 28.8% methyl alcohol, 8.2%THF.B)20％(0.02M?KH
2PO
4，pH?2.5)，80％CAN。Gradient: 100%A) 10min; 100%A) to 25%A) 40min.Solvent: H
2O/ACN, v/v.Concentration: 0.5mg/ml.
The standard substance preparation
(S)-duloxetine of 5-5.5mg-(S)-Naproxen Base (2: 3) eutectic and (the S)-duloxetine HCl standard substance of accurately weighing respectively, and use water dissolution, with H
2O/ACN (v/v) reaches 10ml.
Test sample preparation
(S)-duloxetine of 5-5.5mg-(S)-Naproxen Base (2: 3) eutectic and (the S)-duloxetine HCl specimen of accurately weighing respectively, and use water dissolution, with H
2O/ACN (v/v) reaches 10ml.
Solution is repeated to be expelled under the above-mentioned chromatographic condition.
The detection computations of each product is as follows:
% detection=(sample area * normal concentration * 100)/(standard area * sample concentration)
The result:Having shown the result who obtains in Fig. 7 and Fig. 8, wherein is that each sample is at time of origin and the HPLC collection of illustrative plates after 5 days.In following table 3, summed up the result who obtains:
Table 3:
Conclusion
Under this study condition, (S)-duloxetine-(S)-Naproxen Base (2: 3) eutectic is more stable than (S)-duloxetine HCl.Can observe from the HPLC collection of illustrative plates of Fig. 7 and Fig. 8, wherein (S)-duloxetine-(S)-Naproxen Base (2: 3) eutectic collection of illustrative plates can not change after 5 days, and in the collection of illustrative plates of (S)-duloxetine HCl, some impurity increase.
Embodiment 1e: determine eutectiferous water absorbability of the present invention:
Purpose is to measure the water absorbability of salt of the present invention, and its water absorbability with a kind of known salts of each relative part of salt is compared.Thereby bonded water in the increase assess sample of measurement weight, and the Karl Fischer factor.
According to " Technical guide forthe elaboration of monographs " special issue of the PharmaEuropa (third edition) in December, 1999, based on be exposed in 24 hours 25 ℃ down the weight increase after 80% the relative humidity determine water absorbability.Criterion is as follows:
| % bonded water | ||
| Δ＜0.2％ | No hygroscopicity | |
| 0.2％＜Δ＜2％ | |
|
| 2％＜Δ＜15 | Water absorbability | |
| 15％＜Δ | High-hygroscopicity | |
| Be dissolved in the water | Deliquescence |
Method:
The preparation of humid test case: prepare oversaturated sodium nitrite solution (45g/50ml), put it into (samplaterecord) in the moistening tank.Before using this case remained on 22 ± 2 ℃ following 24 hours of temperature, every day controlling moisture.Condition is: this case has 64 ± 5% relative humidity, and temperature is 22 ± 2 ℃.
Three samples of-preparation:
(S)-duloxetine of the embodiment 1 of sample 1:250mg-(S)-Naproxen Base (2: 3) eutectic,
The duloxetine hydrochloride of sample 2:115mg,
The naproxen sodium of sample 3:102mg.
-these samples are put into the humid test case of control condition, after 24 hours, control weight after 48 hours and after 7 days, up to reaching balance (2 stepless controls, its changes in weight is less than 0.2mg).
-also definite Karl Fischer factor (using Methrom 756KF) when research beginning and end.
The result:
The variation of control weight is also calculated following per-cent:
Δ % weight=(P
n-P
1)/P
1X100
Wherein: P
1Be the initial weight of sample, P
nBe the measurement weight of sample.
In following table 4, summed up the result:
Table 4: changes in weight (%) and Karl Fischer value
| Sample | KF(t＝0) | Δ % weight 24h | Δ % weight 48h | |
| Sample | ||||
| 1 | 0.36 | 0 | 0.09 | ?0.13 |
| |
0.33 | 0.19 | 0.26 | ?0.18 |
| |
1.04 | 14.39 | 14.39 | ?14.3 |
According to aforementioned criterion (scale), wherein naproxen sodium is hygroscopic, (S)-duloxetine of duloxetine hydrochloride and embodiment 1-(S)-Naproxen Base (2: 3) eutectic salt is nonhygroscopic.
Embodiment 2a: obtain the eutectiferous program of (S)-duloxetine-Tolmetin (1: 2)
With Di Iso Propyl Ether dropwise join backflow (S)-duloxetine (289mg, 0.97mmol) and Tolmetin (500mg, 1.94mmol, in ethyl acetate 2eq) (1mL) solution up to begin the precipitation.Then, minimum ethyl acetate is dropwise added up to reaching dissolving fully once more.With this solution cool to room temperature, slowly stirred 48 hours then.The suspension that filtration obtains, with the washing of cold ethyl acetate, in 40 ℃ of following vacuum (10mm Hg) thus produced 1: 2 the eutectiferous solid of (S)-duloxetine-Tolmetin of corresponding ratio (700mg, 89% productive rate) in dry 4 hours.
(S)-sign of duloxetine-Tolmetin eutectic (1: 2 ratio)
By
1H-NMR, X-ray diffraction, DSC and TG fully characterize (S)-duloxetine-Tolmetin (1: the 2) eutectic (seeing Fig. 9 to 10) that obtains according to embodiment 2.
1H NMR (400MHz, d4-methyl alcohol) δ: 2.39-2.50 (m, 7H), 2.61 (m, 1H), 2.71 (s, 3H), 3.21 (m, 1H), 3.31 (m, 1H), 3.68 (s, 4H), 3.93 (s, 6H), 5.96 (dd, J=4.6Hz, J=8Hz, 1H), 6.10 (d, J=4.1Hz, 2H), 6.63 (d, J=4.1Hz, 2H), 6.96 (m, 2H), 7.17 (d, J=3.2Hz, 1H), 7.28 (m, 4H), 7.33 (d, J=5.2Hz, 1H), 7.42 (m, 1H), 7.48 (m, 2H), 7.63 (d, J=8Hz, 4H), 7.79 (m, 1H), 8.30 (m, 1H).
DSC (10 ℃/minute): corresponding to the endotherm(ic)peak (see figure 9) that starts from 111 ℃ of fusing points.
TG (10 ℃/minute): do not observe the weight loss (see figure 9) under the temperature of fusing point being lower than.
Figure 10 has shown eutectiferous powder x-ray diffraction (PXRD) collection of illustrative plates of (S)-duloxetine and Tolmetin.Table 5 is described the peak that is expressed as the d value in detail.
The eutectiferous selection of (S)-duloxetine-Tolmetin peak tabulation that table 5. obtains by powder x-ray diffraction
Claims (16)
1. an eutectic comprises as free alkali or as the duloxetine of its physiological acceptable salt and the eutectic precursor of at least a COX-of being selected from inhibitor class.
2. eutectic according to claim 1, wherein, described eutectic precursor or described eutectic precursor at least a has at least one and is selected from by ether, thioether, alcohol, sulfydryl, aldehyde, ketone, thioketones, nitric ether, phosphoric acid ester, thiophosphatephosphorothioate, ester, thioesters, sulfuric ester, carboxylic acid, phosphonic acids, phospho acid, sulfonic acid, acid amides, primary amine, secondary amine, ammonia, tertiary amine, thiocyanate-(ester), cyanamide, oxime, nitrile, diazo, Organohalogen compounds, nitro, the s-heterocycle, thiophene, the n-heterocycle, the pyrroles, the o-heterocycle, furans, epoxide, superoxide, hydroxamic acid, functional group in the group that imidazoles and pyridine constitute;
Preferred wherein said eutectic precursor or described eutectic precursor at least a has at least one and is selected from functional group in the group that is made of alcohol, sulfydryl, ester, carboxylic acid, primary amine, secondary amine, tertiary amine;
Most preferably wherein said eutectic precursor or described eutectic precursor at least a has at least one and is the functional group of carboxylic acid.
3. according to each described eutectic in the claim 1 to 2, wherein select at least a of described eutectic precursor or described eutectic precursor by this way, that is, if compare with independent duloxetine or with the mixture of duloxetine and corresponding promoting agent,
Described eutectiferous solvability improves; And/or
Described eutectiferous dose response improves; And/or
Described eutectiferous usefulness improves; And/or
Described eutectiferous dissolution rate improves; And/or
Described eutectiferous bioavailability improves; And/or
Described eutectiferous stability improves; And/or
Described eutectiferous water absorbability reduces; And/or
The reduction of described eutectiferous various informative property; And/or
Described eutectiferous form is adjusted.
4. according to each described eutectic in the claim 1 to 3, wherein, one of described eutectic precursor or described eutectic precursor are selected from
Acetylsalicylic acid, diflunisal, ethenzamide, salicylic amide, Triflusal, Fosfosal, Win-11450, paracetamol, propacetamol, phenidine, etofenamate, Flufenamic Acid, meclofenamic acid, mefenamic acid, niflumic acid, tolfenamic acid, acemetacin, oxametacin, indomethacin glucosamide, proglumetacin; bufexamac; diclofenac; W-7320; Aceclofenac; indomethacin; lonazolac; sulindac; Tolmetin; Amtolmetin Guacil; N-22; Bromfenac; nabumetone; fentiazac; felbinac; flurbiprofen; flurbiprofen axetil; Ibuprofen BP/EP; Ketoprofen; Naproxen Base; tiaprofenic acid; zaltoprofen; pirprofen; fenoprofen; Vedaprofen; nepafenac; amfenac; clidanac; Sulpyrine; propyl group quinizine; recheton; mofebutazone; crovaril; Phenylbutazone; Azapropazone; isoxicam; lornoxicam; piroxicam; tenoxicam; ketorolac; Soz 43-715; Evil promazine; ditazole; R-ETODOLAC; meloxicam; nimesulide; celecoxib; rely on former times cloth; Luo Mei former times cloth; Parecoxib; rofecoxib; cut down ground former times cloth; western miaow former times cloth; Bermoprofen; Pelubiprofen; Tenosal; Aceneuramic acid; Pirazolac; Xi Nuoluofen; Fluorine is spreaded out sweet smell; Anirolac; Zoliprofen; Bromfenac; Pemedolac; Dexpemsdolac; Bindarit; Romazarit; Tiaprofenic acid; Ketorolac; Fenbufen; Fenoprofen; Fluorine is spreaded out sweet smell; Taisho); Or its steric isomer, salt or metabolite.
5. according to each described eutectic in the claim 1 to 4, wherein, described eutectic precursor is Naproxen Base, its enantiomer or its salt; Preferred wherein said eutectic precursor is (S)-Naproxen Base or its salt.
6. eutectic according to claim 5, wherein, the molecular ratio between duloxetine and (S)-Naproxen Base is 2: 3.
7. eutectic according to claim 6 is characterized in that, starts from 124 ℃ corresponding to the heat absorption spike of fusing point.
8. eutectic according to claim 6, it is characterized in that, it shows the X-ray powder diffraction collection of illustrative plates, wherein 12.889,10.733,10.527,9.194,8.541,7.594,7.430,6.656,6.444,6.082,5.975,5.754,5.436,5.346,5.259,5.182,5.131,4.953,4.930,4.817,4.766,4.739,4.690,4.654,4.638,4.597,4.434,4.293,4.266,4.174,4.068,4.005,3.984,3.940,3.886,3.795,3.769,3.735,3.715,3.641,3.577, with 3.533 places have be expressed as with
The peak of the d value of meter.
9. eutectic according to claim 6 is characterized in that, it has the following triclinic(crystalline)system structure cell of size:
α＝107.477(3)°
β＝99.792(3)°
γ＝95.382(2)°。
10. according to each described eutectic in the claim 1 to 4, wherein, described eutectic precursor is Tolmetin or its salt.
11. eutectic according to claim 10, wherein, the molecular ratio between duloxetine and the Tolmetin is 1: 2.
12. eutectic according to claim 11 is characterized in that, starts from 111 ℃ corresponding to the heat absorption spike of fusing point.
13. eutectic according to claim 11, it is characterized in that, it demonstrates the X-ray powder diffraction, wherein have at 13.774,12.845,11.510,9.146,8.909,8.462,7.662,6.856,6.435,6.329,6.019,5.881,5.715,5.571,5.259,5.010,4.928,4.888,4.569,4.443,4.274,4.216,4.136,4.032,3.951,3.896,3.830 and 3.757 places be expressed as with
The peak of the d value of meter.
14. be used for producing, may further comprise the steps according to each described eutectiferous method of claim 1 to 13:
(possibility I):
(a) the eutectic precursor is dissolved or suspended in the solvent; With
(b) described solution or dispersion are heated to above envrionment temperature and are lower than the temperature of the boiling point of described solution or dispersion;
(c) in step (a), will be dissolved in the solvent together as the duloxetine of free alkali or salt afterwards or before;
(d) the described solution with (c) joins in the heated solvent of (b), and it is mixed;
Or (possibility II):
(a) eutectic precursor and duloxetine are dissolved or suspended in the solvent; With
(b) described solution or dispersion are heated to above envrionment temperature and are lower than the temperature of the boiling point of described solution or dispersion;
(d) solvent is joined in the heated solvent of (b), and it is mixed; (for possibility I and II) then
(e) mixing solutions/dispersion with step (d) is cooled to envrionment temperature;
(f) leach the eutectic that obtains.
15. pharmaceutical composition is characterized in that, its be included in physiology can accept in the medium the treatment significant quantity according to each described eutectic in the claim 1 to 13.
16. treating pain according to each described eutectic in the claim 1 to 13, preferred acute pain, chronic pain, neuropathic pain, hyperpathia, allodynia or cancer pain comprise the application in diabetic neuropathy or diabetic peripheral neuropathy and osteoarthritis or the fibromyalgia.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP08384009.0 | 2008-05-21 | ||
| EP08384009A EP2123626A1 (en) | 2008-05-21 | 2008-05-21 | Co-crystals of duloxetine and co-crystal formers for the treatment of pain |
| PCT/EP2009/003617 WO2009141144A1 (en) | 2008-05-21 | 2009-05-20 | Co-crystals of duloxetine and cox-inhibitors for the treatment of pain |
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| Publication Number | Publication Date |
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| CN102036946A true CN102036946A (en) | 2011-04-27 |
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| CN2009801179730A Pending CN102036946A (en) | 2008-05-21 | 2009-05-20 | Co-crystals of duloxetine and Cox-inhibitors for the treatment of pain |
Country Status (8)
| Country | Link |
|---|---|
| US (2) | US8501802B2 (en) |
| EP (2) | EP2123626A1 (en) |
| JP (1) | JP2011520933A (en) |
| CN (1) | CN102036946A (en) |
| CA (1) | CA2724812A1 (en) |
| ES (1) | ES2408699T3 (en) |
| MX (1) | MX2010012712A (en) |
| WO (1) | WO2009141144A1 (en) |
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| CN111747947A (en) * | 2020-07-30 | 2020-10-09 | 山东第一医科大学(山东省医学科学院) | Meloxicam-urea eutectic crystal and preparation method thereof |
| CN114685370A (en) * | 2020-12-25 | 2022-07-01 | 成都苑东生物制药股份有限公司 | Butorphanol tartrate crystal form I and preparation method and application thereof |
| CN114404409A (en) * | 2022-02-23 | 2022-04-29 | 江苏海洋大学 | Pharmaceutical composition capable of treating pain and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| US20110160273A1 (en) | 2011-06-30 |
| EP2291345B1 (en) | 2013-03-13 |
| CA2724812A1 (en) | 2009-11-26 |
| US9084774B2 (en) | 2015-07-21 |
| ES2408699T3 (en) | 2013-06-21 |
| US8501802B2 (en) | 2013-08-06 |
| JP2011520933A (en) | 2011-07-21 |
| EP2123626A1 (en) | 2009-11-25 |
| MX2010012712A (en) | 2011-02-15 |
| US20140024697A1 (en) | 2014-01-23 |
| EP2291345A1 (en) | 2011-03-09 |
| WO2009141144A1 (en) | 2009-11-26 |
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